Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Epipodophyllotoxins and anthracyclines, which are commonly used chemotherapeutic DNA topoisomerase II inhibitors, more accurately are called DNA topoisomerase II poisons because they increase the concentration of DNA topoisomerase II cleavage complexes and have the overall effect of enhancing cleavage, which is cytotoxic (1). These agents are associated with leukemia as a treatment complication (2). Most DNA topoisomerase II inhibitor-related leukemias have MLL (myeloid lymphoid leukemia) translocations (3). The translocations disrupt an 8.3 kb bcr between exons 5-11 of the ˜100 kb MLL gene at chromosome band 11q23. The association of DNA topoisomerase II inhibitors with leukemia has suggested a translocation mechanism that involves chromosomal breakage from drug-stabilized DNA topoisomerase II cleavage and formation of the breakpoint junctions when the breakage is repaired (2). The drug stabilized complexes have been called ternary (drug-DNA-topoisomerase II) complexes in the literature. In previous reports, MLL translocations have been characterized and tracked in leukemias in two patients receiving chemotherapy (Megonigal 2000; Blanco 2001), and the role of chemotherapy-stabilized DNA topoisomerase II cleavage in the translocation process has been investigated in in vitro assays of DNA substrates outside of the cellular context (Lovett, 2001; Lovett 2001; Whitmarsh 2003). However, cell death from chemotherapy also forces bone marrow progenitor cell proliferation (4) and native DNA topoisomerase IIα expression is highest in proliferating cells (5, 6).
Genomic breakpoint junctions on derivative chromosomes arising from MLL translocations were cloned in two cases of leukemia following intensive neuroblastoma regimens (7, 8). Such chemotherapy regimens have been associated with a high incidence of leukemia as a treatment complication (9).